The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

/pdf/homeostasis-model-assessment-insulin-resistance-and-beta-119fe0y1fg.pdf

Homeostasis model assessment : insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.

Role of Insulin Resistance in Human Disease

the growth of knowledge regarding the etiology and pathogenesis of diabetes has led many individuals and groups in the diabetes community to express the need for a revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a consequence, it was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease. (1)

Report of the expert committee on the diagnosis and classification of diabetes mellitus

http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

Overall glucose uptake represents the sum of insulin-mediated glucose uptake (IMGU) and non-insulin-mediated glucose uptake (NIMGU). In this study, we compared the rate of NIMGU in conscious and anesthetized dogs. Rates of glucose disposal were compared in the basal state and during severe insulinopenia after endogenous insulin suppression by high-dose somatostatin (SRIF) infusion. Steady-state NIMGU rates were calculated 2 h after commencing SRIF infusion. Three groups of studies were performed: 1) SRIF in conscious dogs; 2) SRIF in anesthetized dogs; and 3) SRIF plus glucagon, also in anesthetized dogs. In all three groups, serum insulin levels were reduced to below assay sensitivity after SRIF infusion. The basal metabolic clearance rate of glucose (MCRg) for each group was 3.8 +/- 0.4, 3.6 +/- 0.3, and 3.6 +/- 0.3 ml X kg-1 X min-1, respectively (P = NS, all groups). Steady-state NIMGU rates were 2.4 +/- 0.2 (conscious), 2.5 +/- 0.1 (anesthetized, SRIF only), and 2.4 +/- 0.1 ml/kg/min (anesthetized, SRIF plus glucagon). Thus, absolute rates of NIMGU expressed as MCRg in conscious and anesthetized animals do not differ and in the three groups studied comprise approximately the same proportion of the basal glucose uptake (approximately 64, approximately 69, and approximately 66%, respectively). We conclude that approximately 66% of basal postabsorptive glucose uptake occurs via NIMGU mechanisms and that this pathway is unaffected by anesthesia and surgery.

Non-insulin-mediated glucose uptake predominates in postabsorptive dogs.

Endogenous adenosine enhances the insulin sensitivity of isolated rat adipocytes. We studied whether this effect was related to an ability of adenosine to alter the activation of insulin receptor kinase by insulin. It was found that depletion of endogenous adenosine by adenosine deaminase treatment decreases insulin–s ability to activate the receptor kinase at submaximal insulin concentrations. This occurred without changes in insulin binding. At 4 ng/ml insulin, adenosine deaminase decreased insulin activation of insulin receptor kinase by 25%, a reduction that equalled the effect of adenosine deaminase on insulin stimulation of 2-deoxyglucose transport. The effects of adenosine deaminase on both insulin activation of insulin receptor kinase and insulin stimulation of 2-deoxyglucose transport were reversed by the addition of N6-phenylisopropyladenosine, a nonhydrolyzable adenosine analog. Our data are consistent with the view that adenosine modulates the coupling of insulin binding to biological actions ...

Adenosine Modulates Insulin Activation of Insulin Receptor Kinase in Intact Rat Adipocytes

The concept that receptors function as recognition sites for polypeptide hormones and neurotransmitters on plasma membranes of target cells originated during the early 1900s.(1) The theory that emerged was that binding of hormone to its receptor on the outer face of the membrane is the initial step in hormonal action, which triggers a transmembrane signal such as generation of a second messenger. This theory has now been expanded, since receptors subserve a greater role in hormone function and metabolism. In addition to hormone recognition, receptors mediate the internalization(2–5) and degradation(6) of hormones. This has been documented for many peptide hormone—receptor systems(7) and the process appears to be similar to receptor-mediated endocytosis of other molecules such as low-density lipoproteins,(8) asialoglycoproteins,(9) and α2-macroglobulins.(10)

The Metabolism of Insulin Receptors: Internalization, Degradation, and Recycling

"Metabolic Bone and Mineral Disorders" aims to provide clinicians with a concise, state-of-the-art update on the diagnosis and management of bone and mineral disorders. It aims to convey pathogenetic, diagnostic and management concepts. Introductory chapters address the major recent advances in the understanding of bone physiology and its regulation by hormones, there is a chapter devoted to the diagnostic procedures with emphasis on the usefulness and limitations of the available biochemical, radiologic and histologic tests and chapters on all the major disorders of bone and mineral metabolism including hyper and hypocalcemia; primary and secondary disorders of the parathyroind gland; disorders of the vitamin D metabolism; Paget's disease; the various forms of osteopenia and osteoporosis; skeletal abnormalities associated with renal disease and some of the most common hereditary disorders of bone metabolism. Special attention has been given to the problem of osteoporosis.

Metabolic Bone and Mineral Disorders

We studied the kinase activity of partially purified insulin receptor preparations from various rat and human tissues. Time courses for in vitro autophosphorylation were determined, and times to reach half-maximal (t½ max) and maximal (tmax) 32P incorporation were compared. Insulin receptors from rat muscle, liver, and fat had a t½ max of 7–10 min and a tmax of 60 min; human-derived insulin receptors had a t½ max in excess of 30 min and a tmax of 120 min. A spectrum of autophosphorylation time courses was present in human tissues; placenta-derived receptors exhibited a t½ max of 13 min while receptors from monocytes and fibroblasts had t½ max values of 60 and 80 min, respectively. The ATP Km for autophosphorylation of human-derived receptors was 5-fold greater than that of rat-derived receptors (266 ± 27 vs. 48 ± 8 μM, respectively). In contrast, when the receptors were first maximally prephosphorylated, the ATP Km values for substrate phosphorylation of human- and rat-derived receptors were equivalent (1...

Jerrold M. Olefsky

Papers

Non-insulin-mediated glucose uptake predominates in postabsorptive dogs.

Adenosine Modulates Insulin Activation of Insulin Receptor Kinase in Intact Rat Adipocytes

The Metabolism of Insulin Receptors: Internalization, Degradation, and Recycling

Metabolic Bone and Mineral Disorders

Functional and Structural Differences in Human and Rat-Derived Insulin Receptors: Characterization of the β-Subunit Kinase Activity*